Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Boenzi, Sara; Deodato, Federica; Taurisano, Roberta; Goffredo, Bianca Maria; Rizzo, Cristiano; Dionisi‐Vici, Carlo

doi:10.1194/jlr.m061978

Cited by 65 publications

(53 citation statements)

References 24 publications

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“…Considering that the specificity of the oxysterol analysis for NPC diagnosis is not fully understood, since oxysterol elevation could also occur in other conditions with high oxidative stress or cholesterol accumulation [18,19,34], the aim of this work was to investigate the potential use of the 3β,5α,6β-triol analysis in the screening of non-newborn patients with clinical suspicion of NPC, correlating the measurements with the results of Filipin test, chitotriosidase activity and molecular analysis. Our data showed that all not-treated patients with positive results in the Filipin test also presented high concentrations of 3β,5α,6β-triol (higher than 100 ng/mL), indicating that the 3β,5α,6β-triol measurement was effective in detecting NPC patients.…”

Section: Discussionmentioning

confidence: 99%

“…Emerging evidence suggest that cholesterol oxidation products, specially 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (3β,5α,6β-triol, or triol), are markedly increased in the plasma of NPC patients, indicating that these products could be used as non-invasive and highly sensitive biomarkers for NPC disease [17][18][19]. These oxysterols are products of non-enzymatic cholesterol oxidation due to an increased oxidative stress process, which was reported in human NPC mutant fibroblasts, in tissues from NPC1 mutant mice and in biological samples from affected patients [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Ribas

Souza

Mari

et al. 2016

Clinica Chimica Acta

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Background: Niemann-Pick type C (NPC) is a treatable genetic disorder, mainly characterized by neurological dysfunction and liver damage. Its diagnosis is based on an invasive test which requires a skin biopsy to demonstrate the cholesterol accumulation in culture fibroblasts of affected patients. In the last years, new biomarkers have been investigated aiming to facilitate the diagnosis and screening of NPC; two of these possible candidates are the oxysterol cholestane-3β,5α,6β-triol (triol), a product of non-enzymatic oxidation of cholesterol, and the enzyme chitotriosidase (CT), a fully active chitinase (EC-3.2.1.14) synthesized by activated macrophages. Methods: In this work, we investigated the potential use of the combined analysis of triol levels and CT activity for diagnosis, screening and monitoring of NPC in Brazilian patients, correlating with the results of Filipin staining and genetic analysis. We studied 122 untreated individuals with clinical suspicion of NPC who were separated in two groups according their concentrations of triol (higher or lower than the cutoff value of 100 ng/mL). We also analyzed blood samples from 5 patients with previous diagnosis of NPC who were under treatment with miglustat. Results:The results of this work demonstrated that patients with higher concentrations of triol (group A) also presented a high activity of CT and most of them had also a positive Filipin test. Two patients of this group presented an inconclusive Filipin test, being one eventually diagnosed as NPC by molecular investigation and the other eventually diagnosed as Niemann-Pick type A or B (NPA/B) by the low acid sphingomyelinase activity presented. Three patients with high triol concentrations who had a negative result in the Filipin test presented low activities of acid sphingomyelinase, being diagnosed as NPA/B. On the other hand, triol concentrations were normal in NPC patients treated with miglustat, although CT activity in these individuals remained abnormal. In the patients with triol lower than 100 ng/mL (group B), most presented a normal activity of CT. No patient of this group had a positive Filipin test and the few patients with inconclusive Filipin test did not present pathogenic mutations in the NPC1 or NPC2 genes. Conclusions: In conclusion, our data demonstrated that the combined analysis of triol and CT is quite sensitive and specific for the identification of NPC patients. Although the number of analysis in NPC patients treated with miglustat was small, the data indicate that the measurement of triol could also be potentially useful for treatment monitoring.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Ribas

Souza

Mari

et al. 2016

Clinica Chimica Acta

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“…NPC can also present challenges to diagnosis due to its wide variability in terms of clinical severity and the age at onset. Laboratory testing options have been limited; promising biomarkers like oxysterols have some shortcomings: they are sensitive to autoxidation, and not very specific because they are increased in neonatal cholestasis [3], in NPA/B and in other cholesterol defects [19][20][21]. The Lyso forms of sphingosine, LysoSM and LysoSM-509, markers of NPA/B, were also increased in NPC, confirming their diagnostic potential for the diagnosis of NPC.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS

Polo

Burlina

Kolamunnage

et al. 2017

Clinical Chemistry and Laboratory Medicine (CCLM)

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Background: Lysosphingolipids (LysoSLs) are derivatives of sphingolipids which have lost the amide-linked acyl chain. More recently, LysoSLs have been identified as storage compounds in several sphingolipidoses, including Gaucher, Fabry and Niemann-Pick diseases. To date, different methods have been developed to measure each individual lysosphingolipid in plasma. This report describes a rapid liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) assay for simultaneous quantification of several LysoSLs in plasma. Methods: We analyzed the following compounds: hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM) and lysosphingomyelin-509 (LysoSM-509). The sample preparation requires only 100 μL of plasma and consists of an extraction with a mixture of MeOH/acetone/H 2 O (45:45:10, v/v). Results: The method validation showed high sensitivity, an excellent accuracy and precision. Reference ranges were determined in healthy adult and pediatric

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“…Indeed, increased levels of 7KC have been reported in the plasma and/or the cerebrospinal fluid of patients with neurodegenerative diseases. Thus far, 7KC has been identified at increased levels in the cerebrospinal fluid of patients with MS [21] as well as in the plasma of patients with X-ALD [22] and Niemann–Pick disease [23]. 7KC has also been detected at higher levels in the plasma of patients with the progressive form of MS than in plasma from patients with the relapsing remitting form of MS [24].…”

Section: Introductionmentioning

confidence: 99%

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

Debbabi

Nury

Zarrouk

et al. 2016

IJMS

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Lipid peroxidation products, such as 7-ketocholesterol (7KC), may be increased in the body fluids and tissues of patients with neurodegenerative diseases and trigger microglial dysfunction involved in neurodegeneration. It is therefore important to identify synthetic and natural molecules able to impair the toxic effects of 7KC. We determined the impact of 7KC on murine microglial BV-2 cells, especially its ability to trigger mitochondrial and peroxisomal dysfunction, and evaluated the protective effects of α- and γ-tocopherol, Trolox, and oleic acid (OA). Multiple complementary chemical assays, flow cytometric and biochemical methods were used to evaluate the antioxidant and cytoprotective properties of these molecules. According to various complementary assays to estimate antioxidant activity, only α-, and γ-tocopherol, and Trolox had antioxidant properties. However, only α-tocopherol, γ-tocopherol and OA were able to impair 7KC-induced loss of mitochondrial transmembrane potential, which is associated with increased permeability to propidium iodide, an indicator of cell death. In addition, α-and γ-tocopherol, and OA were able to prevent the decrease in Abcd3 protein levels, which allows the measurement of peroxisomal mass, and in mRNA levels of Abcd1 and Abcd2, which encode for two transporters involved in peroxisomal β-oxidation. Thus, 7KC-induced side effects are associated with mitochondrial and peroxisomal dysfunction which can be inversed by natural compounds, thus supporting the hypothesis that the composition of the diet can act on the function of organelles involved in neurodegenerative diseases.

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Evaluation of plasma cholestane-3β,5α,6β-triol and 7-ketocholesterol in inherited disorders related to cholesterol metabolism

Cited by 65 publications

References 24 publications

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Selective screening of Niemann–Pick type C Brazilian patients by cholestane-3β,5α,6β-triol and chitotriosidase measurements followed by filipin staining and NPC1/NPC2 gene analysis

Diagnosis of sphingolipidoses: a new simultaneous measurement of lysosphingolipids by LC-MS/MS

Protective Effects of α-Tocopherol, γ-Tocopherol and Oleic Acid, Three Compounds of Olive Oils, and No Effect of Trolox, on 7-Ketocholesterol-Induced Mitochondrial and Peroxisomal Dysfunction in Microglial BV-2 Cells

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